Tuberculosis (TB) continues to be one of the greatest infectious disease threats to human health. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (MTB) further complicate the control of TB (Phillips, L., Nature (2013) 493:14-16, WHO. Global Tuberculosis Report (2012)). To confront these challenges, more effective TB therapies must be developed. Current drug discovery efforts have yielded few new antitubercular drug treatments. In particular, a major challenge lies in understanding the systems-scale consequences that result from perturbing MTB with a drug (Korcsmaros, T., et al., Expert Opin. on Drug Discovery (2007) 2:799-808). It has recently been appreciated that the interconnectivity of biological networks can provide robustness to drug treatment and a tendency to minimize drug impact (Eldholm, V., et al., Genome Biol. (2014) 15:490, Koul, A., et al., Nat. Commun. (2014) 5:3369).
There are now a number of examples of registered drugs that hit specific targets very well but show lower efficacy than expected in vivo due to compensatory responses (Hopkins, A. L., Nat. Biotech. (2007) 25:1110-1111). In particular, the antitubercular drug, bedaquiline (BDQ) received FDA approval in 2012 and has high selectivity for mycobacterial F1Fo ATP synthase, but displays almost no bactericidal activity during the first 4-6 days (Andries, K., et al., Science (2005) 307:223-227, Dhillon, J., et al., Tuberculosis (2010) 90:301-305 and Berney, M., et al., mBio (2014) 5:e01275-01214). Transient MTB tolerance, mediated by regulatory control, could be responsible for the delayed onset of killing by BDQ, and a better understanding of the regulatory mechanisms that effect transition to the tolerant state in response to BDQ should reveal novel hypotheses to improve therapeutic outcomes.
Although the theoretical basis is not entirely clear, it is common for tuberculosis treatment to involve combinations of drugs. For example, US2011/0190199 describes a particular compound which can be used in combination with two other agents that are combined with it and among those that are candidates are PA-824 and BDQ. Similarly, WO2015/107482 describes combinations of the compound of that application with three antitubercular agents which are selected from a list that includes PA-824 and BDQ. In addition, Chatterjee, M., et al., Antimicrob. Agents Chemother. (2014) 58:5325-5331 shows synergy of the compound described therein with PA-824 and BDQ in vitro. Numerous such combinations are known in the art.
It has now been shown that certain transcription factors are responsible for a BDQ-specific tolerant state and by testing the ability of candidate drugs to modulate the activity of these transcription factors, drugs can be identified that will overcome the tolerant state and potentiate the activity of BDQ. By identifying regulatory factors that are associated with the tolerance exhibited by MTB to BDQ, convenient assays have been developed to identify compounds that will potentiate the bactericidal activity of BDQ.